Co-beadlet of dha and rosemary and methods of use

ABSTRACT

The present invention provides improved beadlet formulations useful for inclusion in dietary supplements customized for improving and maintaining ocular nutrition. In particular, the improved beadlets comprise DHA (docosahexaenoic acid); rosemary and/or its components; and excipients.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of nutraceuticals and to theuse of dietary supplements to maintain or improve ocular health.

2. Description of the Related Art

Dietary supplements are recommended for a variety of reasons includingthe improvement of vision or prophylaxis of vision loss. An example ofdietary supplements useful in improving ocular nutrition and promotinghealthy eyes are the ICaps® Dietary Supplements (Alcon Laboratories,Inc., Fort Worth, Tex.). Dietary supplements are generally consumed inthe form of powders, tablets, capsules or gel-caps and comprise avariety of vitamins, minerals, and herbal or other organic constituents.Some dietary supplements are formulated with beadlets, which mayfunction as carriers for the nutritional ingredients and may be blendedand compressed into tablets or filled into capsules or gel caps.

Beadlets which contain dietary substances are generally small spheroidsof less than about a millimeter in diameter. There are a variety offunctions and purposes of beadlets. For example, beadlets may providefor the separate confinement (internal) and segregation fromcomplementary (external) ingredients within the dietary supplement. Thistype of separation can isolate those components with the potential forinteraction or reaction and thereby improve the stability and/or theavailability of either entrapped or complementary external ingredients.The ingredients may be combined into a beadlet with a complementarycomponent which facilitates digestion or absorption improvingbioavailability. More generally, the food industry has utilizedmicroencapsulation to control availability, flavor, or odor andshelf-life and dosage uniformity stability of acidulants, aromas,nutritional oils and supplements, vitamins, minerals, dietary fibers, orleavening agents, and control of moisture, bacterial growth, andbioburden. The chemical industry has utilized the technology fornumerous applications from controlling reaction rates to controllingdistribution.

Various beadlet compositions are known and can be obtained from a numberof food ingredient or supplement manufacturers, chemical orpharmaceutical manufacturers, specialized manufacturers, biotechnologycompanies and research institutes; and from independent universitylaboratories. Particular beadlet compositions for nutritionalapplications have been the subject of numerous patents including U.S.Pat. No. 4,254,100 (Keller et al.) and U.S. Pat. No. 3,998,753(Antoshkiw et al.). Methods of beadlet manufacture have been disclosedin U.S. Pat. No. 4,670,247 (Scialpi) and U.S. Pat. No. 3,998,753.

Microencapsulation can be accomplished in one of several manners, from asimple capsular reservoir in which a particle, like an oil droplet, iscoated with a thin, generally polymeric, coating to a monolithic matrixin which a final porous, commonly polymeric, structure is generated thatcan accommodate an active component in its interstices. In someinstances, such as the technology to be claimed, it has been necessaryto combine the two technologies, providing a coated monolithic activecarrier.

Current beadlet compositions used in dietary supplements generally arerestricted to the use of inert food-grade ingredients and excipientsdetermined to be safe and effective and complementary to a singlenutritional compound. In other instances, when molecules of the sameclass are refined from a particular source, for example a majorcomponent with a minor related constituent, and both compounds produceparallel effects, such molecules may not necessarily be isolated butmixed together in a beadlet. These may be consideredpseudo-single-component beadlets, and there are examples in the marketplace, e.g., Lutrinol® and FloraGLO® beadlets, which are a combinationof lutein and zeaxanthin as formulated in Retoxil® Dietary Supplements.Examples of ingredients benefiting from beadlet confinement haveincluded natural vitamins such as Vitamins A, D, E, and K; minerals suchas iron and sodium bicarbonate; xanthophylls such as lutein, zeaxanthin,canthaxanthin, and astaxanthin; carotenoids and retinoid alone or incombination, such as beta-carotene, lycopene, and retinol.

Pending U.S. patent application Ser. No. 09/397,472 (the '472application, herein incorporated by reference) and related foreignapplications directed to beadlets containing more than one activeingredient. More specifically, those applications are directed to abeadlet containing one or more xanthophylls, one or morecarotenes/retinoids, one or more antioxidants, and one or moresolidifying agents. The beadlets of the '472 application are aimed attreating or preventing mammalian diseases or disorders. The '472application does not discuss the use of DHA or rosemary alone or in anycombination.

The preferred form of administering such compositions is the tablet.Unfortunately, previous attempts to create a beadlet containing DHA andproduce a tablet from the beadlets have resulted in a tablet with aprominent unpleasant marine odor. Further, it was found that thebeadlets themselves, after a short period of time, developed anunpleasant marine odor. Thus, what is needed is a beadlet formulationthat is both substantially odorless and stable, which does notdeteriorate over the shelf life of the product and which can withstandthe compressive forces associated with manufacture, and especially oftableting.

SUMMARY OF THE INVENTION

The present invention overcomes these and other drawbacks of the priorart by providing improved beadlet formulations useful for inclusion indietary supplements. In particular, the improved beadlets comprise DHA(docosahexaenoic acid); rosemary and/or its components; and excipients.The beadlets are particularly useful for incorporation in dietarysupplements customized for improving and maintaining ocular nutrition.

The present invention is also directed to improved dietary supplementscomprising the improved beadlets. Preferred dietary supplements havebeen formulated as an aid to ocular health. The present invention isalso directed to methods of using the beadlets and dietary supplementsfor improving nutritional health. The methods of the present inventionare particularly directed to the enhancement of ocular health and theprophylaxis of retinal disorders, including age-related maculardegeneration.

The application of the beadlet technology of the present invention todietary supplements provides, and facilitates development of, enhancednutritional supplementation. Such technology may aid in increasingbioavailablity of the dietary substances and also provide ease inmodifying compositions containing DHA and rosemary within thesupplement. Such improvements are believed to be particularly useful inthe enhancement of ocular nutrition and improved ocular health.

In certain preferred embodiments, the present invention provides acobeadlet and/or its coating containing docosahexaenoic acid (DHA)and/or rosemary. The DHA will be present in the beadlet in aconcentration of preferably from about 0.1% to about 50% and therosemary will be present in the beadlet in a concentration of preferablyfrom about 0.1% to about 50%. More preferably, the beadlet will containa concentration of DHA of from about 7% to about 25% and a concentrationof rosemary of from about 2% to about 20%. The coating, which serves asa barrier to oxidation from the outside and to escape of odorous agentsor their byproducts from the inside, generally consists of a physicallyor chemically crosslinked or associated polymer and excipients, and mayalso include an agent such as rosemary to mask odors or prevent chemicaldergradation. It will be understood by the skilled artisan that thepercentage ranges above (i.e., 0.1% to 50%, etc.) include all points inbetween said range. That is, it includes 0.2%, 0.3%, 0.4% and so on,1.0%, 1.1%, 1.2% and so on, 5.0%, 5.1%, 5.2% . . . 5.7%, 5.8%, 5.9% andso on up to and including 20%, 25%, 30%, 40%, etc.

The beadlets of the invention are virtually odorless. As used herein,the term “odorless” means that the beadlets of the invention havevirtually no odor. Depending on the sensitivity of the nose, of course,some may detect no odor, some may detect a slight odor, and some maydetect more than a slight odor. The term odorless as used herein is notmeant to require that all beadlets are completely without odor but torequire that the beadlets are substantially without odor. That is, theodor is substantially diminished compared to is beadlets not having thecombination of DHA and rosemary of the present invention.

The DHA for use in the beadlets of the present invention may come fromfish oil or from fermentation of algae, but could also be derived fromflaxseed or soybean or canola oil, borage, eggs or organ meats. Mostpreferably, the DHA for use in the beadlets of the present invention iswithout any significant initial odor, e.g. that from fermentation ofalgae.

The beadlets of the invention may be in the form of capsular reservoiror monolithic matrix. Capsular reservoirs for an oily active, such asthose of the current invention, typically consist of at least onesurface-active agent, such as phospholipids and water-soluble polymers,utilized to stabilize microparticles of the active agent(s) suspended ina medium in which they do not dissolve. The coating may be anyfilm-forming type of coating material, such as carbohydrates (acacia andcellulose derivatives and dextrans to gelatin), gluten, polyesters,starch, lactide-glycolide copolymers, waxes, etc. One of skill in theart may easily select appropriate coatings based on their properties andtheir compatibility with the active component(s) and selected/requiredexcipients.

Monolithic matrices essentially trap the active agent(s) within a “web”of polymer. While the monolithic matrix may be formed using any knownmethod, it will generally be formed by precipitation polymerization,coacervation of polymeric blends, condensation polymerization, or bysimple drying. In certain embodiments, the core of the carrier maycomprise a monolithic matrix while the remainder of the beadlet is acapsular reservoir. In a preferred aspect, the core may be generatedwith acrylates.

The matrix may be loaded with active agent(s) either before or afterpolymerization. Whether loading occurs before or after polymerizationwill depend on the nature of the active agent(s) and/or upon thecapacity of the carrier. Such determinations are well within theknowledge and the skill of the ordinary skilled artisan.

In addition, either type of microparticle may require other excipientssuch as plasticizers, dispersants, colorants and/or opaquants,extenders, and fillers.

Further, where the active agent(s) are unstable it may be furtherdesirable to combine the capsular reservoir and matrix technologies.That is, the active agent(s) may be embeded within a matrix and then thematrix coated to restrict transport of degradizer into the core. Thisembodiment is preferred where one or more of the active agents areantioxidants. In certain preferred aspects, protective antioxidants canbe placed in the core to protect the most vulnerable specie, and mayalso be placed in the coating. Such a coating can serve two purposes:first, the coating isolates the active and may reduce the rate at whichreactive oxygen reaches the active embedded in the core; and second, theantioxidant in the coating serves to reduce the limited amount of oxygenin the head space of the container, generally a plastic bottle oftablets or capsules.

Preferably, the cobeadlet of the invention will include the followingcomponents: two or more active agents; crystallizing or solidifyingcomponents, which may include active agents; polymers, either syntheticor biopolymeric; precipitating coacervating components; fillers, whichmay be inert components, may impart important physical properties to thebeadlet, such as hardness or size characteristics, or may provideimportant chemical characteristics important to one or both of theactives, such as binding or stabilizing characteristics; plasticizers,which prevent the beadlet from being too fragile and crumbling duringprocessing; and chemical agents which protect one or more of the activeagents, improving their stability.

The present invention further provides a method of maintaining orimproving ocular health in a mammal. The method of the inventiongenerally includes admistering to a mammal a composition comprisingco-beadlets, wherein said co-beadlets comprise DHA and rosemary. Inpreferred embodiments, the beadlets for use in the methods of theinvention will be as described above. Typically, the composition for usein the methods of the invention can be administered in many forms,including powder, capsule, caplet, gel cap or tablet. Most preferably,the composition will be administered in the form of a tablet, a tabletalso intended to deliver other micronutrients of value in maintainingocular nutrition.

DETAILED DESCRIPTION PREFERRED EMBODIMENTS

The present invention is directed to improved beadlet formulations,improved dietary supplement formulations comprising the improvedbeadlets and methods of use. As used herein, “dietary supplement(s)” orthe shortened form, “supplement(s),” refer to any finished, dietarysupplement dosage form containing dietary substances and suitable foringestion by a host, e.g., human or other mammal.

Docosahexaenoic acid (DHA) is an ω-3 essential fatty acid derived fromfish oil or by fermentation, such as from algae. Both minor componentsof DHA and the by-products of its oxidation have been observed topossess an objectionable aroma, sometimes described as a “marine odor.”Producers have attempted to eliminate this drawback of the use of DHA bydevising a purer product, by creating carriers capable of protecting theproduct from oxidation, by masking the odor with a more acceptablefragrance (e.g., a citrus fragrance), or a combination of thesetechnologies. For example, both the fermentation process and the isisolation of the DHA from the broth have been improved. The result hasbeen a DHA product that has significantly diminished marine odorrelative to that obtained from fish oil.

To improve stability of that product and maintain the more odor-freestatus, the DHA was encapsulated in a beadlet. In one form, the beadletwas produced using gelatin beadlet technology. The beadleted DHA wasthen formed into a tableted product. When the DHA-containing beadletswere compared with DHA-containing beadlets manufactured using fish-oilderived DHA, a significant improvement in the odor was detected.However, when the beadlets were made into tablets, the marine odor wasprevalent, regardless of the source of the DHA. The marine odor wasfound to increase with time.

Initial studies of tableted formulations of DHA oil indicated that inorder to control the dominant marine odor emanating from the tablets, itwould be necessary to encapsulate this ω-3 fatty acid. Algal DHApossessed a less offensive odor than that derived from fish oil, andbeadlets of the algal DHA were least offensive. However, followingtableting, some of the offensive odor was regenerated. An analagousinstability had been observed with the compression of lutein beadlets .. . only after compression were they observed to be unstable. It isbelieved that the effect of compression was to expose an increasingfraction of the compound to oxidation. The compression of the DHAbeadlets to produce tablets appeared to produce a similar effect;namely, that compression was allowing an increasing fraction of the DHAto be exposed to oxidation, and that it was the oxidized (‘rancid’)product that generated the more offensive odor. Thus, the presentinventor conceived that an antioxidant in sufficient concentration mightserve to protect, or assist in protecting, beadletted DHA exposed to thepressure of tablet compression.

It was known that including antioxidants safe for human consumption,such as tocopherols (vitamin E-related compounds) and ascorbates(vitamin C derivatives), in beadlets with lutein protected the luteinfrom oxidation. Without being bound to any theory, it is believed thatthe antioxidants protect the lutein by behaving in specific ways: (1)all of the oxygen in the head space eventually reacts with antioxidants;(2) any oxygen which diffuses through the plastic bottle also will reactwith the confined antioxidants; (3) the oxygen reacts more rapidly withthe most oxidizable antioxidants. Thus, the antioxidants in the beadletsare “used up” before oxidization can effect the more important activeingredient. While the DHA has been found to be protected by the rapidlyoxidizable components in rosemary, other sources of even more rapidlyoxidizable concentrated botanically derived antioxidant are anticipatedto provide comparable benefit and are envisioned to be encompassed bythe claimed technology.

The present inventor has found that some antioxidants, namely vitamins Cand E and rosemary, are effective in protecting retinas from acutelight-induced toxicity. Cellular antioxidants function in a cascade ofreactions in order to protect sensitive organelles against reactiveoxygen species in metabilizing tissues, in which oxygen eventually isreduced to water. For example, ascorbate is known to regenerate thereduced specie of Vitamin E from the oxidized specie. Therefore, thepresent inventor conceived that rosemary in sufficient quantities in aco-beadlet with DHA might serve multiple purposes. First, it acts as asecond active ingredient, providing protection for the eyes andimproving ocular health. Second, it acts as a “stabilizer,” increasingshelf-life of the product. Finally, it acts as a “de-odorizer,” maskingthe marine-odor of the DHA by preventing its oxidation, and imparting afavorably perceived fragrance.

The present inventor has found that adding rosemary and/or itscomponents to DHA-containing beadlets, such that both “active”ingredients are present in a single beadlet, eliminates the off-odorassociated with oxidized DHA while stabilizing the composition, thusincreasing its shelf-life. It is contemplated that virtually any beadlettechnology, such as that described in U.S. Pat. Nos. 4,254,100;3,998,753; 4,670,247; and 3,998,753 will be useful in the practice ofthe present invention.

Stability of the beadlet in the present context refers to goodcontaining properties, i.e. the encapsulation protects the activecompound(s) from exposure to oxidation and other conditions which mayadversely affect the compound or its subsequent availability. Therosemary within the same beadlet as the DHA provides even furtherprotection of the DHA from oxidation and other conditions which maycause the production of the characteristic unpleasant “marine” odor, andcontributes to its value as an ocular nutrient.

According to a particular embodiment of the present invention, themicroencapsulated DHA/rosemary-containing composition contains 0.1% to40% of DHA, wherein the particle size of the DHA/rosemary beadlets rangefrom about 100 μm to about 600 μm, though occasional large particles upto 800 μm and small fines of as small as 10 μm may be acceptable aswell. The microencapsulated compositions of the present invention aresuitable for tablet preparation, hard shell capsule filling andincorporating in different foods. According to a particular embodimentof the present invention, the DHA/rosemary mixtures employed herein mayfurther comprise fillers, excipients or additives. Examples of suitablefillers include starch, pectins, carrageenans, xanthan gums, proteins,polyethylene glycols, cellulose derivatives (e.g., methyl cellulose,hydroxypropyl cellulose and ethyl cellulose) and other polysaccharides.

The present invention is advantageous in that it describesmicrocapsules, or beadlets, containing DHA and rosemary having virtuallyno offensive odor, with improved stability, relatively high content ofthe active agents and improved bioavailability of the active agents. Theadvantages of the claimed invention derive from the presence of theDHA/rosemary mixtures together in the same beadlet thus decreasing oreliminating offensive odors and increasing stability and shelf-life. Themicrocapsules of the present invention are tablet grade, i.e., suitablefor use in tableting. Preferred compositions of the present inventionare gelatin free.

The beadlets of the invention are capable of protecting the activeagents (DHA and rosemary) from oxidative damage accompanying exposure tooxygen in the package headspace and/or transported across the packagebarrier during the shelf-life storage of the product. The beadlets ofthe invention are further capable of withstanding the compressive forcesof 15 SCU or greater and preferably 20 SCU or greater occurring duringtableting so that the confined antioxidants of the final product arecompromised neither in stability nor in efficacy.

The present invention additionaly provides a composition of the dosageform, containing both the beadlets with the properties defined above aswell as other antioxidants themselves (which may or may not be confinedin beadlets), such that the most oxidizable component, generally theantioxidants found in rosemary, is present in sufficient abundance toreact and deactivate the oxygen in the head space, and protect all ofthe remaining antioxidants (carotenoids, xanthophylls, vitamins, otherpolyphenolics, etc.). The amount of rosemary in the body of the tablet(not included in the amount contained in/on the carrier beadlet [above])generally will be greater than 3 mg/tablet and preferably greater than 5mg /tablet when these tablets are packaged conventionally in bottles of60 tablets and the container is LDPE or the equivalent in oxygentransmissability, and the protective antioxidant is unfortified rosemaryoil. As will be well understood by those trained in the art, the amountmay be reduced if concentrated forms of the reactive antioxidants inrosemary are utilized. The amount of rosemary in the body of the tabletpreserves activity of all the tablet antioxidants, whereas the rosemarycontained within the beadlets provides nutritional and therapeuticvalue, as well as stabilization for the beadlet.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Excipients for Gelatin-Based Cobeadlets

In the following examples of the technology, actives and coactives referto DHA and rosemary, or the components thereof. Specific examples of thetechnology include composition of the cobeadlets, composition of anoptional coating, and ingredients and excipients contained in a completetablet. Examples of cobeadlets include: Core Coactives   15% Vegetableoil and Oleoresin 18.5% Hydrolyzed Gelatin 27.5% Sucrose   12% AscorbylPalmitate   3% Coating Rosemary (LycoRose)   3% Coating Corn Starch andcellulose   16% Water   5%

EXAMPLE 2 Excipients for Nongelatin-Based Cobeadlets

Core Coactives:   24% Sodium alginate: 24.8% Isolated soy protein: 16.5%Silicon dioxide:   2% Coating Hydroxypropyl cellulose (Klucel) 14.5%Coating Herbalox type O (rosemary)  4.8% Lyc-o-rose (rosemary):  1.9%Ethoxylated glycerides:  4.8% Sucrose ester:  1.9% Water and Ca:   ˜5%

EXAMPLE 3 Examples of the Coating Technology

Excipients for a coating of cobeadlet cores, especially for anon-gelatin based core Active or Coactives 3% Hydroxypropylcellulose 16%Methanol 30% Acetone 51%

A. Excipients for a coating of cobeadlet cores, especially for agelatin-based core Active or Coactives 4% Corn Starch 10% Cellulosic 22%Water 60%

EXAMPLE 4 Examples of Actives in Tablet and Capsule Formulations Usefulfor Maintaining Ocular Health

A. Actives in an ophthalmic formulation Icaps Rev 3 Formula Ingredient(per tablet) Units Vitamin A 2,500 IU (β-carotene) 1.5 Mg Vitamin B-2 5Mg Folate 100 μg Vitamin B-12 3 μg Vitamin C 200 Mg Vitamin E 75 IUCopper 0.5 Mg Manganese 5 Mg Selenium 20 μg Zinc (acetate) 7.5 Mg Lutein(max) 2 Mg Zeaxanthin (min) 1 Mg DHA (docosahexaenoic 5 Mg acid[22:6ω3]) Rosemary (minimum) ≦5 Mg

B. Actives & excipients (indented) in an ophthalmic formulation:Ascorbic Acid   Gelatin   Hydroxypropyl Methylcellulose dl-AlphaTocopherol Acetate   Dicalcium Phosphate   Microcrystalline Cellulose  Magnesium Stearate   Sucrose   Silicon Dioxide Zinc Acetate DihydrateManganese Amino Acid Chelate   Corn Starch   Water   Sodium alginateSelenium Amino Acid Chelate   Soy protein (isolated)   Titanium Dioxide  Hydroxypropyl cellulose (Klucel)   Fatty acids (DHA excipients) DHA(in oil carrier) Copper Amino Acid Chelate Riboflavin   PolyethyleneGlycol Lutein/Zeaxanthin   Water and Ca   Ethoxylated glycerides  Ascorbyl Palmitate Beta Carotene Rosemary (from Herbalox type O)  Sodium Ascorbate   dl-Alpha Tocopherol Zeaxanthin   Canola oil(Herbalox excipient)   Soybean oil (Herbalox excipient)   Excipients  Sorbic Acid   Polysorbate 80   Sodium Benzoate Folic Acid   Vegetableoil (Lyc-o-Rose excipient)   Carnauba Wax Cyanocobalamin

EXAMPLE 5

Manufacture of tablets from the microcapsules described in Examples 1and 2. The ingredients, all core actives and excipients including thecobeadleted DHA and rosemary, are blended and granulated to form ahomogenous mass, which is stored in nearly full, low-headspace, sealedplastic bags. As quickly as possible, eliminating any significantdelays, the blend is tableted to a hardness of approximately 22 SCU, andthe tablets again stored in nearly full, low-headspace, sealed plasticbags until the tablets can be coated, a hiatus that will be kept to aminimum. The tablets are finally spray coated, dried, and packaged.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically and structurallyrelated may be substituted for the agents described herein to achievesimilar results. All such substitutions and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope andconcept of the invention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

U.S. Pat. Nos.

-   -   3,998,753    -   4,254,100    -   4,670,247

1. A cobeadlet comprising docosahexaenoic acid (DHA) and rosemary. 2.The cobeadlet of claim 1, wherein said beadlet is odorless.
 3. Thecobeadlet of claim 1, wherein said DHA is obtained by fermentation fromalgae.
 4. The cobeadlet of claim 1, further comprising at least oneantioxidant other than rosemary.
 5. The cobeadlet of claim 1, whereinthe concentration of DHA is from about 0.1% to about 50% and theconcentration of rosemary is from about 0.1% to about 50%.
 6. Thecobeadlet of claim 5, comprising from about 7% to about 25% DHA and fromabout 2% to about 20% rosemary.
 7. A method of maintaining or improvingocular health in a mammal, said method comprising administering to saidmammal a composition comprising co-beadlets, wherein said co-beadletscomprise DHA and rosemary.
 8. The method of claim 7, wherein saidcomposition comprises from about 0.1% to about 50% DHA and about 0.1% toabout 50% rosemary.
 9. The method of claim 8, wherein the composition isin the form of a tablet.
 10. A tablet comprising the cobeadlet ofclaim
 1. 11. The tablet of claim 10, further comprising as excipientsoutside of the cobeadlets, at least 3 mg rosemary oil.
 12. The tablet ofclaim 11, wherein the tablet comprises at least 5 mg rosemary oil.